1. Field of the Invention
The present invention relates to compounds useful for treating pathological states, which arise from or are exacerbated by cell proliferation, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting cell proliferation in a mammal.
2. Description of the Art
Neoplastic diseases, characterized by the proliferation of cells, which are not subject to normal cell proliferating controls, are a major cause of death in humans and other mammals. Cancer chemotherapy has provided new and more effective drugs to treat these diseases and has also demonstrated that drugs, which are inhibitors of cyclin-dependent kinases are effective in inhibiting the proliferation of neoplastic cells.
Regulators at cell cycle checkpoints determine the decision for a cell to proceed through the cell cycle. Progression of the cell cycle is driven by cyclin-dependent kinases (CDKs) which are activated by oscillating members of the cycin family, resulting in substrate phosphorylation and ultimately cell division. In addition, endogenous inhibitors of CDKs (INK4 family and KIP/CIP family) negatively regulate the activity of CDKs. Normal cell growth is due to a balance between activators of CDKs (cyclins) and endogenous inhibitors of CDKs. In several types of cancer, aberrant expression or activity of several components of the cell cycle has been described.
Cdk4 functions in G1 phase of the cell cycle and is activated by D-type cyclins, which results in substrate phosphorylation and progression to S phase. The only known substrate for cdk4 is the retinoblastonia gene product (pRb), a major tumor suppressor gene product, which functions as a major checkpoint control in regulation of the G1/S phase transition. Hyperphosphorylation of pRb by CDKs causes the release of E2F (a family of transcription factors) bound to pRb which then activate genes necessary for cell cycle progression, e.g. thymidine kinase, thymdylate synthase, cyclin E and cyclin A. Cycin DI is amplified or overexpressed in many types of cancer (breast, ovarian, bladder, esophageal, lung, lymphoma), while the gene for p16, the endogenous inhibitor of cdk4, is deleted, mutated, or aberrantly methylated in many tumor types. A point of mutation in cdk4 was reported in a melanoma tumor that rendered the enzyme unable to bind p16 resulting in a constitutively active enzyme. All of the conditions described above lead to activation of cdk4 and cell cycle progression and tumor cell growth.
Arguments to designate CDK2 as an anticancer agent can be found in the literature <<Cyclin E activates Cdk2 which acts to phosphorylate pRb resulting in an irreversible commitment to cell division and transition into S-phase>> (P. L. Toogood, Medicinal Research Reviews (2001), 21(6); 487–498. and <<CDK2 (and possibly CDK3) is required for G1 progression and entry into S phase. In complex with cyclin E, it sustains pRb hyperphosphrylation to support progression through G1 and into S phase. In addition many other cellular targets of CDK2-CyclinE have been identified . . . . In complex with cyclinA, CDK2 plays a role in inactivating E2F and is required for completion of S phase.>> T. D. Davies et al. (2001) Structure 9, 389–397.
An added level of regulation of CDK activity exists. Cyclin-dependent kinase activating kinase (CAK) is a positive regulator of CDKs. CAK phosphorylates the catalytic CDKs on a conserved threonine residue to render the target enzyme completely active.
Because the defects in cell cycle molecules lead to CDK activation and subsequently cell cycle progression, it is logical that inhibition of CDK enzyme activity should block cell cycle progression and tumor cell growth.
The first CDK inhibitor to enter clinical trials is the compound known as flavopiridol. This compound is currently in Phase II clinical trials and is the only molecule in its class in the clinic at the present time. The aim of this invention is to produce molecules more active than flavopiridol.
It is known following publication of WO00/41669 that benzimidazole carbamate derivatives are vascular damaging agents that can be used for treating cancer, the sulfonic acid ester derivatives claimed in this patent application are not at all exemplified and their anticancerous way of action is not described. Our invention relates specifically to carbamates of those sulfonic acid ester derivatives.